Webb R L, Abramson M L, Beil M E, Odorico L M, Chatelain R E
Metabolic and Cardiovascular Diseases, Novartis Pharmaceuticals Corp, Summit, New Jersey 07901, U.S.A.
J Cardiovasc Pharmacol. 1997 Nov;30(5):632-42. doi: 10.1097/00005344-199711000-00014.
This study examined the long-term effects of CGS 30440 on blood pressure, heart rate, cardiac hypertrophy, and urinary parameters in conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Initial studies with CGS 30440 produced dose-related reductions in mean arterial pressure, with a dose of 30 mg/kg/day of CGS 30440 producing a maximal sustained response of 40 mm Hg. CGS 30440 significantly inhibited plasma angiotensin-converting enzyme (ACE) activity by 82% in WKY rats. In SHRs, lung ACE and renal neutral endopeptidase (NEP) were inhibited by >60 and >90%, respectively. Urinary cyclic guanosine monophosphate (cGMP) excretion was significantly increased by CGS 30440 in SHRs but was unaltered in WKY rats. One hour after the final dose of an 8-week regimen, blood pressure was 122 +/- 4 and 189 +/- 5 mm Hg in CGS 30440-treated (30 mg/kg/day) and vehicle-treated SHRs, respectively. Heart-rate responses were not different between treatment groups. Left ventricular hypertrophy (LV weight/body weight ratio) was reduced significantly in SHRs to 2.45 +/- 0.08 mg/g at 10 mg/kg/day and 2.26 +/- 0.07 mg/g at 30 mg/kg/day versus 2.91 +/- 0.09 mg/g in rats receiving only vehicle. These results demonstrate that CGS 30440 is a potent, orally active antihypertensive agent with a long duration of action. The cardiac hypertrophy of established hypertension in the SHRs was attenuated by CGS 30440. Thus CGS 30440, an orally active prodrug, has been shown to be a novel antihypertensive agent with dual ACE/NEP inhibitory activity in SHRs.
本研究考察了CGS 30440对清醒自发性高血压大鼠（SHRs）和Wistar-Kyoto（WKY）大鼠的血压、心率、心脏肥大及尿液参数的长期影响。对CGS 30440的初步研究显示，其能使平均动脉压呈剂量依赖性降低，剂量为30 mg/kg/天时，CGS 30440产生的最大持续反应为40 mmHg。在WKY大鼠中，CGS 30440可使血浆血管紧张素转换酶（ACE）活性显著抑制82%。在SHRs中，肺ACE和肾中性内肽酶（NEP）分别被抑制>60%和>90%。CGS 30440使SHRs的尿环磷酸鸟苷（cGMP）排泄显著增加，但对WKY大鼠无影响。在8周给药方案的最后一剂后1小时，CGS 30440治疗组（30 mg/kg/天）和溶剂对照组SHRs的血压分别为122±4 mmHg和189±5 mmHg。各治疗组之间的心率反应无差异。与仅接受溶剂对照的大鼠相比，在SHRs中，左心室肥大（左心室重量/体重比）在10 mg/kg/天时显著降低至2.45±0.08 mg/g，在30 mg/kg/天时降低至2.26±0.07 mg/g，而后者为2.91±0.09 mg/g。这些结果表明，CGS 30440是一种强效的口服活性抗高血压药物，作用持续时间长。CGS 30440可减轻SHRs中已建立的高血压所致的心脏肥大。因此，CGS 30440作为一种口服活性前药，已被证明是一种在SHRs中具有双重ACE/NEP抑制活性的新型抗高血压药物。
